The prodrug approach is a well-established strategy to improve physicochemical, biopharmaceutic and pharmacokinetic properties of potential drug molecules. Approximately 5-7% of drugs approved worldwide are prodrugs with annual sales in 2013 of $11.2 billion. Most prodrugs are simple chemical derivatives of the original molecule. Ester prodrugs, the most common prodrugs, constitute 49% of all marketed prodrugs. Reasons for the popularity of ester prodrugs include their generally straight forward synthesis, their improved lipophilicity and membrane permeability, and the ubiquitousness of estereases. An example of an approach to make an ester prodrug is capping the acidic moiety(ies) with lipophilic alkyl or alkyloxymethyl esters (i.e., pivaloyloxymethyl (POM) or propyloxycarbonyloxymethyl (POC); e.g., Enalapril, Adefovir). Another approach is to cap the acidic moiety(ies) with amino acids to make amides that are recognizable by transporters, such as Peptide transporter 1 (PEPT1) (e.g., Pomaglumetad methionil, Valacyclovir).
PSMA (Prostate Specific Membrane Antigen), also termed GCPII (glutamate carboxypeptidase II) and FOLH1, is a metallopeptidase that catalyzes the hydrolysis of N-acetylated aspartate-glutamate (NAAG) to N-acetyl aspartate (NAA) and glutamate and cleaves terminal glutamate moieties sequentially from folate polyglutamate (Ristau et al., 2013; Mesters et al., 2006; Slusher et al., 2013). One of the most potent, selective, and efficacious PSMA inhibitors is 2-PMPA (Ki or IC50=300 pM). After 50-100 mg/kg intraperitoneal injection (i.p.) doses, it achieves 30-50 μM concentrations in the brain and provides efficacy in over 20 animal models of the central nervous system (CNS) or peripheral nervous system (PNS) including diabetic neuropathy, peripheral neuropathy, neuropathic pain, general pain, stroke, drug addiction, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), schizophrenia, epilepsy and several others associated with pathological increase of glutamate concentration leading to excito-toxic effects and neuronal death. However, 2-PMPA is a highly polar compound with multiple carboxylates and a zinc binding group and it has negligible oral availability. Therefore, in most cases, it must be dosed intravenously, intraperitoneally, or locally to achieve the desired effects. This fact limits its potential use as a drug since most of the above disorders require long term dosing for which the oral route is strongly preferred.